Executive Summary : | Photopharmacology is a new and emerging area of research where optimal photocontrol of biomolecules is targeted by the introduction of a photosensitive moiety into the signalling molecules. Azobenzene photoswitches have been widely used as a molecular photoswitch to control biomolecules and materials via irradiation of light. Despite the wide variety of applications, researchers are facing several challenges in designing and synthesizing efficient photoswitchable drugs for the photocontrol of biomolecules due to several reasons. One of those important reasons is incomplete photoconversion due to non-radiative decay via internal conversion or intersystem crossing which needs understanding of excited state at the electronic structure. To overcome these challenges, new design strategies are needed. Multiscale computational study on photoswitchable drugs in biomolecules can provide detailed systematic understanding at the atomistic or even electronic structure levels which will help in obtaining design principles for efficient drugs for optimal photocontrol. Understanding properties and functions of photoswitchable drugs in biomolecules using computational methods is very much unexplored in science both nationally and internationally. The PI has previously worked on the investigation of azobenzene as a molecular photoswitch for the photoregulation of RNA using combined QM/MM-surface hopping dynamics. Recently, the PI group have focussed on investigation of local non-covalent interactions, long-range conformational changes and allostery in G-protein coupled receptor upon serotonin binding. This project perfectly blends the idea of the above-mentioned two projects to proceed further in the direction of design principles of photoswitchable drug for G-protein coupled receptors. The aim of this project is to obtain a detailed systematic understanding of the azobenzene-attached photoswitchable serotonin for the optimal control of serotonin receptor signalling using a multiscale computational method. A combination of quantum mechanical methods, combined quantum mechanical/molecular mechanical method as well as classical molecular dynamics simulation will be used for the detailed understanding of the photoswitching process at different length and time scale. This way, we will be able to understand the photoswitching phenomena in gas phase and condensed phase as well as the effect of photoswitching on the signalling molecule at the short and long time scale. The outcome of the project can be summarized and extended to obtain design principles for efficient photoswitchable drugs for G-protein coupled receptors. |